Synthesis and evaluation of DOTHA2 and NODHA2 bifunctional chelators bearing methyl-hydroxamic acid arms
Bibliographic record
Abstract
120 Objectives With the goal of identifying improved bifunctional chelates (BFCs) that stably complex with fast kinetics Cu-64, we have synthesized DOTHA2 and NODHA2, two cyclic BFCs derived from polyazacycles and bearing methyl-hydroxamic acid donor groups as pendant arms. The aim of this research was to assess the suitability of these new 64Cu-labeled BFCs for PET imaging. Methods DOTHA2 and NODHA2 were synthesized both in solution and on solid phase. Radiolabelling experiments were performed varying the pH, the conterion and the temperature to optimize the radiochemical yield. Each chelate has been compared to currently used BFCs DOTA and NOTA with respect to radiolabeling efficiency and stability. We also prepared a series of alternative DOTHA2- and DOTA-bombesin (BBN) conjugates labeled with Cu-64 and measured in vitro receptor binding affinities in human prostate cancer PC3 cells expressing the gastrin-releasing peptide receptor (GRPR) and compared their in vivo stability in mice. Results DOTHA2 and NODHA2 were prepared with greatly yields and ease of synthesis. These BFCs offered fast labelling kinetic at pH 7 and room temperature as compared to their acetic acid analogs DOTA and NOTA (Figure 1a). Under very mild conditions, DOTHA2 and NODHA2 complexes are formed in 5 min using 64CuCl2 or 64Cu(OAc)2 and in 15-20 min with 64Cu-copper oxalate (Figure 1a). DOTHA2, NODHA2 and NOTA displayed high stability in mouse plasma (Figure 1b) and in vivo. Specific activities varied from 76 to 101 TBq/mmol. Competition assays on PC3 cells showed that Cu/DOTHA2-BBN and Cu/DOTA-BBN complexes retained high affinity for the GRPR. However, in vivo, the 64Cu/DOTHA2-BBN complex remained intact after 20 h while the 64Cu/DOTA-BBN complex was completely demetalated. Conclusions In vitro and in vivo stability assays confirm that 64Cu-labeled DOTHA2 and NODHA2 complexes remain stable over the 20 h time period. Our results also show that 64Cu-labeled DOTHA2-BBN conjugate is a promising radiotracer for PET imaging of many human cancers overexpressing GRPR. Research Support CIHR
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".